Heparic sulfite oxidase, located in the inter-membrane space of mitochondria, is essential for the detoxification of SO3 and SO2. It contains 2 atoms of Mo and 2 molecules of cytochrome b5 type heme per dimeric molecule of 115,000 daltons, and uses cytochrome c as the physiological electron acceptor. It is proposed to carry out a detailed structure-function study on the enzyme from rat liver in order to probe mechanisms of intra-molecular and inter-molecular electron transfer. Molybdenum-free sulfite oxidase and xanthine oxidase will be used for investigating the chemistry and biology of a molybdenum cofactor. Attempts will be made to solubilize the cofactor activity located on the outer membrane of rat liver mitochondria and to search for the existence of a postulated non-protein organic moiety in the cofactor. Studies on the cofactor will be of great significance because of the apparent universality of a common molybdenum cofactor in all molybdoenzymes, irrespective of the origin or the reaction catalyzed. The information gained from these studies are directly applicable to the understanding of the genetic basis of human sulfite oxidase deficiency. Studies on the reconstitution of apo xanthine oxidase and on the dehydrogenese yields oxidase conversion will be of direct relevance to human diseases such xanthinuria, gout and Lesch-nyhan disease. The laboratory has also been investigating the nature of metallothionein and copper-chelatin, which are low molecular weight proteins induced in rats exposed to various metals. Further studies on these proteins will try to identify physiological functions for these proteins, and could provide information relating to human genetic diseases like Wilson's disease and Menke's Kinky-hair disease, involving errors in trace element metabolism.